This invention is concerned with a novel method of treating antihypertensive agent-induced sedation by the administration of piperazinyl-imidazo[1,2-a]pyrazines of general structure I which are selective .alpha..sub.2 -adrenergic receptor antagonists. ##STR1##
The piperazinyl group is particularly ubiquitous among compounds with useful pharmacological properties. Piperazinylpyrazines (U.S. Pat. Nos. 4,081,542 and 4,082,844), piperazinylquinoxalines (Belgian Pat. No. 817,608), 2-piperazinyl-5 (and/or 6)-substituted pyridines (U.S. Pat. No. 4,078,063) and piperazinyl-imidazo[1,2-a]pyrazines (U.S. Pat. No. 4,242,344), the compounds useful in the novel method of treatment of this invention, are known anorexigenic agents which are also said to have antidepressant activity by virtue of their pharmacological influence on serotonin levels.
Now, with the present invention there is provided a novel method of treating antihypertensive anti-induced sedation by the administration of these piperazinyl-imidazo[1,2-a]-pyrazines, which are .alpha..sub.2 -adrenergic receptor antagonists.
Sedation, a limiting side effect produced by some antihypertensive agents, is associated with stimulation of presynaptic .alpha..sub.2 -adrenergic receptors. However, the lowering of blood pressure by these agents is not related to stimulation of these receptors, but rather to postsynaptic adrenergic receptors (Birch et al., Br. J. Pharmacol., 68, 107P (1979)). Accordingly, selective .alpha..sub.2 -receptor antagonists are useful in reducing the adverse effect of sedation produced by antihypertensive drugs. Thus, the selective .alpha..sub.2 -receptor blocker, yohimbine, antagonizes the sedation produced by clonidine (Drew et al., Br. J. Pharmacol., 67, 133 (1979)) and the locomotor depressant effects of methyldopa in rats (Clineschmidt et al., Arch. Int. Pharmacodyn. Ther., 244, 231 (1980)). In addition, yohimbine has been reported to reduce clonidine-induced sedation in man (Autret et al., Eur. J. Clin. Pharmacol., 12, 319 (1977)).
The compounds useful in the novel method of treatment of the present invention, being highly selective for the .alpha..sub.2 -adrenergic receptor, effectively reduce the sedative effects of antihypertensive agents without affecting the blood pressure lowering properties. Combinations of antihypertensive agents with selective .alpha..sub.2 -adrenergic receptor antagonists form an additional aspect of this invention.